Social interactions in humans and other mammals are significantly impacted by olfactory signals. For example, semiochemicals (chemosensory stimuli that communicate information between organisms; e.g., pheromones or social cues) can promote mating or aggression behaviors or can contribute to transmission of food preferences between individual mice. However, the molecular, cellular and neural mechanisms underlying olfactory-mediated social interactions remain poorly understood. This proposal will examine the role of a distinct olfactory subsystem within the main olfactory system, the GC-D+ neuron/necklace glomeruli subsystem, in the detection of semiochemicals and the mediation of social interactions related to food preference. GC-D+ neurons differ from canonical olfactory sensory neurons in the transduction-related proteins they express (e.g., the receptor guanylyl cyclase GC-D) and in their olfactory forebrain targets (the necklace glomeruli of the posterior main olfactory bulb). GC-D+ neurons appear to function as multimodal chemosensors, exhibiting responses to a small group of chemostimuli including urine, the natriuretic peptide hormones uroguanylin and guanylin, and to CO2. Anatomical studies suggest that necklace glomeruli also receive diverse chemosensory inputs through heterogeneous afferent innervation and extensive intrabulbar connections with other olfactory glomeruli. Thus, the GC-D/necklace subsystem may be ideally suited to integrate semiochemical and general odor information and may act as coincidence detectors for multiple chemosensory stimuli. We propose a multidisciplinary, collaborative study to investigate the role of the GC- D/necklace subsystem in the detection of semiochemicals as they relate to social interactions. Our proposed study will (1) use molecular biological, electrophysiological and Ca2+-imaging approaches to characterize the responses of GC-D+ neurons to several semiochemicals; (2) use neuroanatomical tracing, immunohistochemistry and electron microscopy to characterize those neurons that provide sensory input to the necklace glomeruli, as well as the central targets of necklace-associated projection neurons; and (3) examine contributions of GC-D+ neurons to important social behaviors, the social transfer of food preference (STFP) and food source preference. Deficits in normal social interactions are a hallmark of autism and many other neurological disorders. Because of this, assays of social interactions such as STFP have been utilized in the study of mouse models of autism. Thus, results obtained here will not only elucidate key mechanisms underlying olfactory-mediated social communication, but should provide important insights into those diseases, such as autism, that show deficits in normal social interactions. PUBLIC HEALTH RELEVANCE: Deficits in normal social interactions are a hallmark of autism and many other neurological disorders. Social interactions in humans and other mammals are significantly impacted by olfactory signals. However, the molecular, cellular and neural mechanisms underlying olfactory- mediated social interactions remain poorly understood. Results obtained here will not only elucidate the mechanisms underlying olfactory-mediated social communication, but should provide important insights into those diseases, such as autism, that show deficits in normal social interactions.